Clinical relevance of pre‐ and coseasonal sublingual immunotherapy with a 300 index of reactivity 5‐grass SLIT tablet in allergic rhinoconjunctivitis

Abstract Background There is considerable interest in improving the scoring methods for evaluating the efficacy of allergen immunotherapy (AIT) and to show if this is associated with clinically meaningful results from the patient's perspective. We aimed to assess the efficacy and clinical relevance of a 300 index of reactivity (IR) 5‐grass pollen sublingual immunotherapy (SLIT) tablet in children, adolescents and adults with moderate to severe grass‐induced allergic rhinoconjunctivitis (ARC) with or without controlled asthma using the combined symptom and medication score CSMS0‐36. Methods The data of the European population that participated in 3 Phase III, international, randomized double‐blind placebo‐controlled clinical trials were analyzed post hoc. Results A total of 864 patients randomized to 300 IR 5‐grass tablet or placebo were analyzed. Over the primary evaluation period, the difference in CSMS0‐36 between the 300 IR and placebo groups was statistically significant (point estimates: −2.51, CI95% [−3.88; −1.14], p < 0.0001 in clinical trial1; −2.31, CI95% [−3.39; −1.23], p < 0.0001 in CT2; and −2.31, CI95% [−3.58; −1.03], p = 0.0004 in CT3). The relative differences between the 300 IR 5‐grass tablet and placebo were −29.7%, −33.8%, and −26.3%, respectively. The results based on CSMS0‐36 were consistent with those obtained with the primary endpoints of the trials and support the consideration of the 2‐point threshold of the CSMS0‐36 for clinical relevance of AIT. Conclusion Post hoc analysis of 3 CTs with the 300 IR 5‐grass SLIT tablet confirmed its significant and clinically relevant effect in the European population with grass pollen‐induced ARC with or without controlled asthma.

One of the commonest symptomatic chronic diseases worldwide with increasing prevalence, allergic rhinoconjunctivitis (ARC) is induced by the IgE-mediated inflammatory response in sensitized individuals after allergen exposure 1 and results in a chronic, mostly eosinophilic, inflammation of the nasal mucosa and conjunctiva. 2Despite the recommended symptomatic treatment, about one fifth to one third of these patients still suffer from uncontrolled nasal and/or ocular symptoms, with a high impairment on quality of life, decreasing work productivity, social interactions, and other aspects of life. 3,42][13][14] Here we present the post hoc analysis in the European population of three randomized, double-blind placebo-controlled trials (DBPCT) with the 300 IR 5-grass tablet in different age groups (children, adolescents and adults).
We aimed to confirm the efficacy of the 300 IR daily dose of this SLIT tablet in grass pollen ARC using a standardized and globally harmonized method for analyzing the clinical efficacy of AIT products in randomized controlled trials.The recommended method by a Task Force of the European Academy of Allergy and Clinical Immunology (EAACI) Immunotherapy Interest Group for optimal endpoints in AIT trials for ARC, in line with both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines, uses a homogeneous combined symptom and medication score (CSMS, scale 0-6) as the primary outcome. 15The score considers symptoms as well as medication in a balanced relation and enables a comparison of the daily burden of the disease between different clinical trials. 15In addition, we examined how the treatment effect versus placebo translates into a clinically relevant improvement perceivable by the patients.

| Study design and patients
[13][14] Briefly, the efficacy of the 300 IR 5-grass SLIT tablet administered around 4 months prior to the pollen season and continued for its duration was evaluated versus placebo in 3 randomized DBPCTs (ClinicalTrials.govnumbers: NCT00367640 (CT1), NCT00418379 (CT2) and NCT00409409 (CT3)).Participants with moderate-tosevere grass pollen-induced ARC with or without controlled asthma were aged 18-45 years in CT1 and CT2, whereas children and adolescents aged 5-17 years were included in CT3.Patients were treated pre-coseasonally over a single year in CT1 and CT3 or discontinuously over 3 consecutive years in CT2.In this trial, the primary evaluation period was at Year 3 and patients were followedup during 2 subsequent treatment-free years.
The three DBPCTs were conducted in Europe.CT2 was also carried out in Canada and Russia, where participants accounted for less than 15% of the overall study population.In this post hoc analysis, we focussed on the European population to ensure data consistency as it has been acknowledged that differences in patients' clinical characteristics and variations in allergen exposure across regions might interfere with the trial results. 16,17om an ethical standpoint, the three DBPCTs were performed in accordance with good clinical practice defined by the International Council for Harmonization and the principles that have their origin in the Declaration of Helsinki and local laws and regulations.All participants or parents or legal representatives (for participants 17 years or younger) gave their written consent to participation after being informed of the trial objectives and procedures.

| Study endpoints and new assessment score
The EAACI-recommended CSMS 15 reflects the symptom severity as well as the intake of rescue medication considering a stepwisesimplified approach based on the clinical effects of pharmacotherapy on symptom reduction.The recommended scoring system for the CSMS is based on an equal weight of the total daily symptom score (dSS) and the total daily medication score (dMS).The dSS uses a well-defined and easy-to-understand terminology for nasal symptoms (itchy nose, sneezing, runny nose, blocked nose) and conjunctival symptoms (itchy/red eyes, watery eyes).Each symptom score ranges on a 0-3 scale as follows: 0 = no symptoms; 1 = mild symptoms (sign/symptom clearly present, but minimal awareness; easily tolerated); 2 = moderate symptoms (definite awareness of sign/ symptom that is bothersome but tolerable); 3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping).The maximum score for the total dSS (sum of the individual symptom scores) is 3 (i.e.18 points/ divided by 6 symptoms) = dSS 0-3 . 15A stepwise use of rescue medication is summed up in the dMS based on the Allergic Rhinitis and its Impact on Asthma in collaboration with the World Allergy Organization (WAO) recommendations in giving rescue medication. 4,18cordingly, the score assigned for each medication is 1 for oral and/ or topical (eyes or nose) non-sedative H1 antihistamines (H1A); 2 for intra-nasal corticosteroids (INCS) with/without H1A; 3 for oral corticosteroids with/without INCS, with/without H1A.The total dMS ranges from 0 to 3 (maximum score) = dMS 0-3 .
Consequently, the total daily CSMS ranges on a 0-6 scale: The 3 DBPCTs captured all the necessary information so that it was possible to assess the efficacy of the 5-grass tablet in this post hoc analysis using the recommended CSMS.Based on the daily diary cards completed by the patients, the rhinoconjunctivitis total symptom score (RTSS 0-18 ) equivalent to the dSS without dividing by 6, and the rescue medication score (RMS 0-3 ) equivalent to the dMS with the same stepwise approach were calculated over the pollen period.The average RTSS 0-18 over the pollen period was the primary endpoint for CT1 and CT3. 12,14Another symptom score was also analyzed in the DBPCTs, the adjusted symptom score (AdSS 0-18 ), which adjusted the RTSS for rescue medication use).Briefly, the AdSS 0-18 took into account the highest RTSS score on the preceding day and applied it to the day on which the rescue medication was taken and the following day. 19The average AdSS 0-18 over the Year 3 pollen period was the primary endpoint in CT2. 13 For analyzing the proposed CSMS in the 3 DBPCTs, we calculated the balanced score on a scale from 0 to 36 as follows: daily CSMS 0-36 = [daily RTSS 0-18 þ (daily RMS 0-3 )*6].

| Statistical model
As per the primary endpoints of the respective studies, an analysis of covariance (ANCOVA) was used to statistically assess the CSMS 0-36 over the primary period (i.e. the pollen period while on treatment in CT1 and CT3 and the Year 3 pollen period in CT2) in a modified Intention-to-Treat (ITT), defined as all patients who received at least one dose of the investigational product and had recorded the primary efficacy measure on at least one day during the primary period.The ANCOVA model used treatment as the main effect, pooled study centre as the stratification factor and age, gender, sensitization, and asthma status as covariates.A point estimate and 95% confidence interval (CI) for the difference in the adjusted least square (LS) means between the active treatment and placebo groups were calculated.
The relative LS mean difference (%) was calculated as follows: 100 � (LS mean 300 IR-LS mean placebo)/LS mean placebo.For the analyses, the probability of type I error (α) was set at 0.05.All inferential tests were two-sided.Statistical analysis was performed using SAS software, version 9.4 (SAS Institute, Inc).

| Clinical relevance
The clinical relevance of the treatment effect (i.e. the reduction in symptom and medication score with the 300 IR 5-grass tablet vs. placebo over the primary period) can be defined as the smallest reduction in the combined score likely to be important from the patients' perspective.The probability of the reduction in the score actually observed in the 3 CTs was calculated from the reduced centred normal distribution of the LS mean differences in average CSMS 0- 36 .Furthermore, the observed reduction in CSMS 0-36 in the 3 CTs was translated into a clinically relevant improvement by considering either component of the combined score: RTSS 0-18 or RMS 0-18 .The reduction in RTSS 0-18 was correlated with a decrease in symptom severity, while the reduction in RMS 0-18 was correlated with a decrease in the number of days with less therapy for a patient taking antihistamines or nasal corticosteroids daily over the pollen period.

| Average CSMS 0-36 during the primary period
Over the primary evaluation period of each trial, statistically significant absolute LS mean differences in the average CSMS 0-36 were observed between the 5-grass tablet and placebo: point estimate p = 0.0004) in CT3 (Table 1 and Figure 1).The relative LS mean differences versus placebo were −29.7%, −33.8%, and −26.3%, respectively.

| Clinical relevance
In all 3 CTs, the probability of a reduction in the CSMS 0-36 of at least 2 points was 76.7%, 71.3%, and 68.2% as estimated from the reduced centred normal distribution of the LS mean differences in the average CSMS 0-36 .This reduction was also translated into a clinically relevant improvement from the patients' perspective.Looking at the RTSS 0-18 component, a reduction of at least 2 points may reflect over the pollen period a decrease of 1 severity class (from severe to moderate, from moderate to mild or from mild to no symptoms) in 2 symptoms or a decrease of 2 severity classes (from severe to mild, from moderate to no symptoms) in 1 symptom, considering the other symptoms and rescue medication intake remain stable (Figure 2).
Looking at the RMS 0-18 component, a reduction of at least 2 points may reflect around 10 days less therapy per month or 1 month less medication per 3 months over the pollen period for a patient taking antihistamines or nasal corticosteroids daily, considering that all symptoms remain stable (Figure 3).

| DISCUSSION
Allergen immunotherapy reduces symptoms as well as the use of medication in the allergic individual. 2,7In evaluating its efficacy in allergic diseases like grass pollen allergy in clinical trials, the recommended balanced combined score CSMS considers both the  Abbreviations: AdSS 0-18 , adjusted symptom score (scale 0-18); CSMS 0-36 , combined symptom and medication score (scale 0-36); CT, clinical trial; IR, index of reactivity; LS, least square; mITT, modified intention-to-treat; n, number of patients in the mITT; RMS 0-3 , rescue medication score (scale 0-3); RTSS 0-18 , rhinoconjunctivitis total symptom score (scale 0-18). a The average RTSS 0-18 during the pollen period was the primary endpoint in CT1 and CT3. b The average AdSS 0-18 during the Year 3 pollen period was the primary endpoint in CT2.
symptoms and medication intake.Because the use of rescue medication that is provided for ethical reasons has an impact on symptom severity/scores, it must be recorded daily and included in the scoring system according to the stepwise approach recommended by the WAO. 20In addition, the scores for symptoms and medication have to be balanced.All these requirements have been considered in the scoring system proposed by the EAACI task force. 15Using such a standardized scoring system gives the opportunity to directly compare different clinical trials.
The DBPCTs with the 300 IR 5-grass tablet in children, adolescents and adults with grass pollen ARC with or without controlled asthma have demonstrated significant clinical efficacy, sustained efficacy and carry-over effect using pre-specified symptom scores as primary variables.Hence, the present post hoc analysis focussed on assessing the clinical efficacy of this grass SLIT tablet using the EAACIrecommended combined score. 15Noteworthy, as the CSMS 0-6 was not yet universally used by all companies evaluating their product (different scales can be noted), it was assumed a 2-point difference in score in the active group versus placebo that can be considered a relevant threshold for clinical relevance could be better perceived on a larger scale 0-36 (i.e. by multiplying the RMS by 6) rather than on a 0-6 scale (i.e. by dividing the RTSS by 6).The results showed a relative difference between 300 IR 5-grass tablet and placebo in CSMS 0-36 over the primary period of −29.7%, −33.8%, and −26.3% in CT1, CT2, and CT3, respectively.Using this new scoring system, the observed magnitude of effect is consistent between the CTs as well as with that observed on their respective primary endpoints (−28.2%,3][14] The treatment effect corresponding to the reduction in CSMS 0-36 between the 300 IR 5-grass tablet and placebo is similar in all age groups (children, adolescents and adults) and in the European population compared to the overall population, as shown in CT2.Moreover, this positive effect appears to increase over time with 26%-30% observed on the first pollen period in CT1 and CT3 and 34% on the third pollen period in CT2.
Combined score results with another grass pollen SLIT tablet, the SQ-standardized grass (Phleum pratense) allergy immunotherapy tablet (ALK-Abelló, Hørsholm, Denmark), were reported from a randomized DBPC, multinational, phase III trial including adults (18-65 years old) with moderate-severe grass pollen-induced ARC. 21In this trial, patients received 3 years of continuous treatment, starting PFAAR ET AL.
[11][12][13][14] CT1 and CT3 were conducted following recommendations from the EMA 'Guideline on the Clinical Development of Medicinal Products for the Treatment of Allergic Rhino-conjunctivitis' (EMA/CHMP/EWP/2455/02, 2004) as to use patient selfrated symptom scores for primary efficacy measurement.Since then, the EMA 'Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases' was issued, recommending the use of a primary variable reflecting the treatment effect on both the symptoms and use of symptomatic medications (EMA/CHMP/EWP/18504/2006, 2008).While CT1 andCT3 were already completed, the long-term CT2 was ongoing, and the study protocol was amended in the second year to opt for a primary endpoint reflecting both measures: the average AdSS 0-18 .19Though this score was accepted by European regulatory authorities, the comparison of treatment effect with other products in the field remained difficult since there was no clear guidance for combining symptoms and medication use leaving the room for using different methodologies.

4- 8 F I G U R E 3
months prior to the first pollen season.In this trial, a weighted rhinoconjunctivitis combined score (RCS) was calculated based on the 6 daily rhinoconjunctivitis symptom scores (total score ranging from 0 to 18) and the daily rhinoconjunctivitis symptomatic medication score (total score ranging from 0 to 36).The weighed RCS was reduced by −33% and −36% relative to placebo in the first and third grass pollen seasons, respectively.21These results with a different combined score construct are consistent with those observed with the 300 IR 5grass tablet following 1 and 3 years of pre-coseasonal treatment in adults (involving ca.6 months treatment per year, rather than continuous treatment), starting ca. 4 months prior to the first pollen season.Noteworthy, when the total combined score was calculated by simply summing the rhinoconjunctivitis symptom and medication scores (=TCS 0-54 ), a similar relative reduction versus placebo was F I G U R E 2 Schematic overview of the clinical relevance of the observed reduction in the average RTSS 0-18 (modified intention-totreat (mITT)).Schematic overview of the clinical relevance of the observed reduction in the average RMS 0-18 (modified intention-totreat (mITT)).